High-resolution myelin-water fraction and quantitative relaxation mapping using 3D ViSTa-MR fingerprinting

Purpose: This study aims to develop a high-resolution whole-brain multi-parametric quantitative MRI approach for simultaneous mapping of myelin-water fraction (MWF), T1, T2, and proton-density (PD), all within a clinically feasible scan time. Methods: We developed 3D ViSTa-MRF, which combined Visualization of Short Transverse relaxation time component (ViSTa) technique with MR Fingerprinting (MRF), to achieve high-fidelity whole-brain MWF and T1/T2/PD mapping on a clinical 3T scanner. To achieve fast acquisition and memory-efficient reconstruction, the ViSTa-MRF sequence leverages an optimized 3D tiny-golden-angle-shuffling spiral-projection acquisition and joint spatial-temporal subspace reconstruction with optimized preconditioning algorithm. With the proposed ViSTa-MRF approach, high-fidelity direct MWF mapping was achieved without a need for multi-compartment fitting that could introduce bias and/or noise from additional assumptions or priors. Results: The in-vivo results demonstrate the effectiveness of the proposed acquisition and reconstruction framework to provide fast multi-parametric mapping with high SNR and good quality. The in-vivo results of 1mm- and 0.66mm-iso datasets indicate that the MWF values measured by the proposed method are consistent with standard ViSTa results that are 30x slower with lower SNR. Furthermore, we applied the proposed method to enable 5-minute whole-brain 1mm-iso assessment of MWF and T1/T2/PD mappings for infant brain development and for post-mortem brain samples. Conclusions: In this work, we have developed a 3D ViSTa-MRF technique that enables the acquisition of whole-brain MWF, quantitative T1, T2, and PD maps at 1mm and 0.66mm isotropic resolution in 5 and 15 minutes, respectively. This advancement allows for quantitative investigations of myelination changes in the brain.

To estimate MWF, conventional MWF mapping relies on a multi-echo spin-echo or gradient-echo sequence (22) and multi-compartment fitting of the exponential decay signal to extract the shorter relaxation time of myelin water (14,22,24).However, the acquisition time of the conventional method is long (e.g., 1 minute per 1 mm slice (22)), and the fitting process is ill-conditioned and susceptible to noise.To improve MWF mapping, Visualization of Short Transverse relaxation time component (ViSTa) technique (25) was proposed for direct visualization of myelin water signal.This technique employs a specifically configured double inversion-recovery sequence that suppresses the long T1 component while preserving the signals from the short T1 components of myelin water.This allows for direct and precise imaging of myelin water, enabling accurate assessment of myelin content without fitting.However, ViSTa faces challenges such as decreased SNR due to signal suppression and a long acquisition time (40 seconds per slice with 1mm 2 even with 9x parallel imaging acceleration achieved via advanced wave-CAIPI techniques (26)).
Magnetic resonance fingerprinting (MRF) (27) is a rapid quantitative imaging technique that simultaneously estimates multiple tissue parameters and has garnered significant interest as a diagnostic tool in various diseases (28)(29)(30)(31).This technique was initially proposed using a 2D acquisition.Since then, numerous studies have focused on advancing MRF to achieve shorter scan times, higher resolutions, improved accuracy and reduced variability.To enable fast high-resolution MRF for whole-brain quantitative imaging, 3D stack-of-spiral (32,33) and spiral-projection-imaging trajectory (34) have been developed.These advancements allow for whole-brain 3D MRF at 1 mm isotropic resolution in ~6 minutes.On the reconstruction side, various methods such as parallel imaging (32,35), low rank/subspace model (36)(37)(38)(39) and deep learning methods (40)(41)(42) have been incorporated into MRF reconstruction to enhance image quality.Recently, MWF mapping has been conducted using modified MRF sequences that aims to achieve better signal separability between myelin water and other tissue types (5,43).However, the extraction of MWF still relies on multicompartment fitting, which can pose challenges in accurately separating different components, particularly in highly undersampled MRF data with low signal-to-noise ratio (SNR).The multicompartment fitting is ill-posed and typically requires additional assumptions and/or priors to obtain good results, which could create bias or artifacts.
This is an open area of research, where a number of innovative reconstruction algorithms (44)(45)(46)(47) are being developed to tackle this issue.
In this work, we have developed a novel 3D ViSTa-MRF acquisition and reconstruction framework that integrates the ViSTa technique into MRF.This approach achieves a remarkable acceleration of MWF mapping by 30x compared to the gold standard ViSTa approach (1.3 seconds per slice with 1mm 3 resolution) while also enabling better SNR and simultaneous estimation of T1, T2, and PD.With the double inversion prep in 3D ViSTa-MRF, we can directly visualize MWF image once the timeseries data is reconstructed, without the need for multicompartment modeling.We demonstrate that the proposed method achieves high-fidelity whole-brain MWF/T1/T2/PD maps at 1mm and 0.66 mm-isotropic resolution in 5 minutes and 15.2 minutes, respectively.Furthermore, we propose a 5-minute whole-brain 1mm-iso ViSTa-MRF protocol to quantitively investigate brain development in early childhood.This work is an extension of our earlier work, which was reported as conference abstract and oral presentation in the Annual Meetings of International Society of Magnetic Resonance in Medicine (ISMRM) 2022 (48).A water-exciting rectangular (WE-Rect) hard pulse (49) was employed for signal excitation, where the RF duration was set to 2.38ms at 3T so that the first zero-crossing of its sinc-shaped frequency response is at the main fat-frequency (440 Hz).In each ViSTa-block, specifically configured double-inversion-recovery pulses were applied (TI1=560ms, TI2=220ms), and the first subsequent signal time-point was referred to as the "ViSTa signal".Twenty consecutive time points were acquired within each ViSTablock to facilitate joint spatial-temporal subspace reconstruction.Through extendedphase-graph (EPG) (50) simulation, Figure 1(B) shows that the myelin-water signal was preserved in the ViSTa signal, while the white-matter (WM), gray-matter (GM) and Cerebrospinal fluid (CSF) were suppressed, which enabled direct myelin-water imaging.At the end of the ViSTa-block, a BIR-4 90° saturation-pulse with a spoiler gradient was applied to suppress flow-in CSF and vessel signals.A waiting time (TD) of 380ms was selected to achieve a steady-state longitudinal magnetization of the short-T1 signal for the next ViSTa preparation.To enhance the encoding of the short-T1 signal, the sequence repeated the ViSTa-block eight times, followed by an MRF block, resulting in a total acquisition time of 19 seconds for each acquisition group.Increasing the number of ViSTa blocks yielded more ViSTa signal encodings but extended acquisition time.To establish the optimal number of required ViSTa blocks, we undertook empirical tests using varying quantities of ViSTa blocks and assessed the reconstructed ViSTa image quality to guarantee its likeness to the standard ViSTa sequence.Through our experiments, we identified that employing 8 ViSTa blocks struck the ideal balance between ViSTa signal quality and acquisition duration.In the last ViSTa-block, the saturation pulse and TD time were omitted to ensure a smooth signal transition between the ViSTa block and the MRF block.This step was taken to standardize the signal across all eight ViSTa blocks and to prepare for obtaining the ViSTa signal, which was not required in the last block.After the ViSTa-blocks, 500time-point FISP-MRF (51) block were acquired.Unlike conventional MRF acquisition, where the inversion-recovery pulse was placed at the beginning of the MRF block.In this approach, we introduced a 1-second rest time before applying the inversionrecovery pulse at the 200th time-point of the MRF block.This design allows for the recovery of longitudinal magnetization after ViSTa preparations.Between the acquisition groups, a BIR-4 90°-saturation-pulse with a TD of 380ms was used to suppress flow-in CSF and vessel signals and achieved steady-state longitudinalmagnetization of short-T1 signal.

Synergistic subspace reconstruction
We proposed a memory-efficient fast reconstruction that leverages spatial-temporal subspace reconstruction (36)(37)(38)54) with optimized k-space preconditioning (55).The ViSTa-MRF dictionary, accounting for B1 + variations (B1 + range [0.70:0.05:1.20]),was generated using EPG, and the first 14 principal components were chosen as the temporal bases (Figure 2(A)).Compared to our previous study (39), where only 5 bases were selected in the subspace reconstruction for a conventional MRF sequence, in ViSTa-MRF, 14 bases were used in the present ViSTa-MRF study to better represent the myelin-water signal.This change was due to the sequence design of ViSTa-MRF, which introduced more signal variations through CRLB optimization.To determine the number of bases needed for the reconstruction, we applied two conditions: (i) Ensuring that the number of bases is sufficient to represent 99% of the signal in the dictionary.
(ii) Conducting empirical tests with different numbers of bases and examining the quality of ViSTa signal to ensure that it resembles the results obtained from the standard ViSTa sequence.The ViSTa-MRF time-series was projected onto the subspace, resulting in 14 coefficient maps based on the selected temporal bases.The ViSTa-MRF time-series x is expressed as x=Φc, where Φ are the temporal bases, c are the coefficient maps.Figure 2(B) illustrates the flowchart of the subspace reconstruction with locally low-rank constraints, which could be described as: where S contains coil sensitivities, F is the NUFFT operator, M is the undersamplingpattern,  is the regularization-parameters. We implemented a novel algorithm in SigPy(56) to solve Equation [1] that combined polynomial preconditioned FISTA reconstruction with Pipe-Menon density-compensation (55) and basis-balancing (57) to reduce artifacts and accelerate the subspace reconstruction.The off-line reconstruction package is available at https://github.com/SophieSchau/MRF_demo_ISMRM2022.With this reconstruction approach, the whole-brain 14-bases coefficient maps (e.g., 220x×220y×220z×14bases for 1mm-iso MRF data) can be efficiently reconstructed on a GPU with 24 GB VRAM in 45 minutes (~90s per iteration, 30 iterations with polynomial preconditioning).This provides a significant improvement compared to reconstruction performed using e.g., , [2] where S(myelin_water) is the B1 + corrected, EPG-simulated signal intensity from the dictionary using nominal T1 and T2 values of myelin-water (T1/T2 =120/20ms).The S(myelin_water) signal is normalized to '1', where the term '1' denotes the maximum signal tipped down by a 90-degree excitation pulse from a fully recovered Mz.
Using spatiotemporal subspace reconstruction, the entire time-series was jointly This capability would not have been achievable with, for example, sliding window NUFFT reconstruction (59).
By utilizing the reconstructed quantitative T1, T2, and PD maps, we can synthesize multiple contrast-weighted images using Bloch equation that provide robust contrasts while significantly reducing scan time and improving motion-robustness during examinations.

In-vivo acquisition and reconstruction
We implemented 1.0 mm and 0. For the 0.66mm resolution, the maximum gradient strength was 60mT/m, and the maximum slew rate was 160T/m/s.Sixteen and forty-eight acquisition-groups with eight ViSTa-blocks were acquired for 1-mm and 0.66-mm cases, respectively, to achieve sufficient spatiotemporal encoding.This resulted in scan times of 19s×16=5 minutes for the 1mm-iso and 19s×48=15.2minutes for the 0.66mm-iso datasets.FOVmatched low-resolution (3.4mm×3.4mm×5.0mm)B0 maps were obtained using multiecho gradient-echo sequence.To mitigate B0-induced image blurring from the spiral readout, a multi-frequency interpolation (MFI) technique (39,60) was implemented in subspace reconstruction with conjugate phase demodulation.To achieve robustness to B1 + inhomogeneity, B1 + variations were simulated into the dictionary and incorporated into the subspace reconstruction.Bloch-Siegert method was utilized to obtain FOVmatched low-resolution B1 + maps (3.4mm×3.4mm×5.0mm).These low-resolution B1 + maps were then linearly interpolated to match the matrix size of the high-resolution ViSTa-MRF results, as the B1 + maps are spatial smoothing.As the ViSTa-MRF dictionary included B1 + effects, the obtained B1 + maps were used to select a subdictionary for matching at each pixel, thus corrected for B1 + inhomogeneity related T1 and T2 bias in ViSTa-MRF (61).The quantitative maps with and without B1 + corrections were compared.
The 20 adult datasets were acquired from five scanners.To test the cross-scanner comparability, we selected the data from one Prisma scanner as the reference.To calculate the cross-scanner mean T1, T2, and MWF values, 32 representative WM and GM regions, along with 5 representative MWF regions were chosen.Using these mean values, the reproducibility coefficient (RPC) and Bland-Altman plots for T1, T2, and MWF were computed.
In order to assess the performance of the CRLB-optimized protocol, we acquired the ViSTa-MRF sequence using both the original FAs and the CRLB-optimized FAs.The original FAs and the CRLB-optimized FAs are depicted in Figure 3 = 56s per slice.The acquisition was not accelerated with parallel imaging as the reconstructed image with full sampling was already at low SNR.This is much slower than ViSTa-MRF, as the proposed 1mm-iso ViSTa-MRF could acquire 220 slices in 5 minutes (1.3s per slice).To validate the accuracy of T1 and T2 estimation of the ViSTa-MRF method, the proposed method is compared with the standard 3D MRF sequence at 1mm isotropic resolution.
In addition to validating our approach on healthy adult volunteers, data were also acquired on two infants to quantitatively investigate infant brain development using MWF, T1 and T2 maps.A 5-minute whole-brain ViSTa-MRF and a T1-MPRAGE (magnetization-prepared rapid gradient echo) with 1.0 mm-isotropic resolution were utilized to acquire data on a 4-month and a 12-month infant.The protocol parameters of the T1-MPRAGE sequence for the baby scans are: TR/TE= 6.9/2.3ms,inversion time = 400ms, flip-angle=11°, image resolution 1×1×1mm 3 , FOV= 220×220 ×220mm

Ex-vivo scans
Additional data were also acquired on ex-vivo brain samples where long scan time is feasible to investigate capability of ViSTa-MRF for investigation of mesoscale quantitative tissue parameter mapping.To validate the image quality of the proposed method, a coronal slab from a 5-month-old post-mortem brain and a left occipital lobe sample from a 69-year-old post-mortem brain were acquired with ViSTa-MRF at 0.50mm-isotropic resolution: FOV:160×160×160mm 3 , 180 acquisition-groups were acquired with total acquisition time of 19s×180=57minutes.For the ex-vivo scans, a lower acceleration rate than feasible was used to ensure high SNR.ViSTa-MRF across four representative WM-regions: genu corpus callosum, forceps minor, forceps major and corpus callosum splenium, are consistent with the literature results (25).The MWF comparison between literature values and our proposed ViSTa-MRF method is shown in Table S1.The region of interest (ROI) size is 5×5 for the four WM regions.

Results
Figure 6 displays whole-brain 660μm T1, T2, PD, ViSTa, and MWF maps obtained within a 15-minute scan time.The zoom-in figures highlight the enhanced ability to visualize subtle brain structures, such as the caudate nucleus (red arrows in Figure 6).
When compared to the 1mm results, the higher resolution of the 660μm dataset provides improved visualization of the periventricular space (red arrows in Figure S2).
Figure S3 shows the cross-scanner comparability of ViSTa-MRF data acquired from 5 scanners and the Bland-Altman plots for T1, T2, and MWF.The results demonstrate robust ViSTa-MRF results across different scanners.

Discussion
In this work, we developed a 3D ViSTa-MRF sequence with a CRLB-optimized FAs and a memory-efficient subspace reconstruction to achieve high-resolution MWF, T1, T2, and PD mapping in a single scan.Compared to the accurate yet time-consuming standard ViSTa sequence, the proposed fast ViSTa-MRF approach provides consistent MWF values at 30x faster scan time with higher SNR.We demonstrate that the proposed method achieves high-fidelity whole-brain MWF, T1, T2, and PD maps at 1mm-and 0.66mm-isotropic resolution on 3T clinical scanners in 5 minutes and 15.2 minutes, respectively.Furthermore, our preliminary results of the 5-minute infant scans demonstrate the feasibility in using this technology for investigating brain development in early childhood.
Previous studies (28,(44)(45)(46) have demonstrated that MRF emerges as a promising multi-contrast acquisition strategy capable of estimating multi-compartment quantitative tissue parameters within a shorter duration.However, it has been recognized that conventional MRF techniques may have limited sensitivity to tissue compartments characterized by short T1 values, such as the myelin water component in brain tissue (66).To address this limitation, several methods have been proposed to modify the MRF sequence.For example, the incorporation of ultra-short-TE acquisition (12) has been used to extract and differentiate the ultra-short T2 component of pure myelin from the long T2 component of myelin-water signals (67).Additionally, a multiinversion preparation with short inversion times has been added to the MRF sequence to improve the sensitivity of the short T1 myelin-water signal (5,43).These modifications aim to enhance the accuracy and specificity of MRF in quantifying myelin-related tissue property.However, these approaches still have limitations, as they either require multi-component fitting (e.g., non-negative least squares with joint sparse constraints (45,46)) or rely on strong assumptions of predefined compartments with fixed T1 and T2 values (5).These assumptions can be sensitive to noise or may introduce biases in MWF quantification.In contrast, our proposed ViSTa-MRF method with CRLB optimization demonstrates promising sensitivity to short T1 components, a single pool without the magnetization transfer effect, which could lead to a potential underestimation of T1 and T2 values.
In this work, we employed the CRLB for the optimization of the ViSTa-MRF sequence.The optimized flip angle for the first time-point was determined to be 38°, which differs from the standard ViSTa sequence that uses a 90° excitation.This variation is attributed to the differences in the acquisition methods.In this study, we also successfully applied the proposed ViSTa-MRF method for exvivo scans.The obtained results from the 5-month-old and 69-year-old brain samples provided valuable insights into the myelination process during early brain development and the demyelination process in the aging brain.As part of our future work, we plan to further investigate the relationship between the estimated MWF and myelin-stained ex-vivo slabs at different cortical depths.This quantitative analysis will enable a comprehensive comparison and validation of our ViSTa-MRF-based myelin water measurements with histological myelin-stained samples.
In developing infant brains, rapid changes in relaxation times present challenges in acquiring sufficient contrast in T1-weighted images for cortical segmentation and surface-based analysis (4,6,71,72).Our ViSTa-MRF technique offers an effective solution to overcome this challenge.By utilizing the quantitative T1, T2, and PD maps, we can synthesize T1-weighted images that provide robust contrasts while significantly reducing scan time and improving motion-robustness during infant examinations, which is beneficial to generate infant substructure segmentation map.This improvement in image quality holds great promise for more accurate infant brain segmentation (73).Furthermore, the multi-contrast-weighted images synthesis eliminates the need for time-consuming structural scans in infant studies and provides an alternative when motion artifacts compromise the quality of conventional contrastweighted images.Currently, we are utilizing quantitative maps and conventional Bloch simulations to synthesize multi-contrast weighted images, which may not fully capture magnetization transfer effect in the synthesized images (74).To address this limitation, we plan to explore the use of deep-learning based methods (75-77) for direct image synthesis from the raw k-space data in our future work, which could achieve faster and more accurate image synthesis.

Conclusion
In this work, we have developed a 3D ViSTa-MRF technique that combines the accurate but time-consuming ViSTa technique with MR fingerprinting for whole-brain multi-parametric MRI.This approach enables us to obtain whole-brain 1mm and 660μm isotropic myelin-water fraction, quantitative T 1 , T 2 and PD maps in 5 and 15 minutes, respectively.These advancements provide us with great potential to quantitatively investigate infant brain development and older adult brain degeneration.

Figure 1 (
Figure 1(A) shows the sequence diagram of the ViSTa-MRF acquisition, where each acquisition group consists of multiple ViSTa-preparation blocks and one MRF-block.
the popular BART software(58) which requires over 1TB of RAM and reconstruction time of over 4 hours on our Linux server for this same problem.This advancement allows for fast reconstruction of large spatial-temporal data, providing more efficient processing.As shown in Figure2(B) and (C), the reconstructed coefficient maps (c) were then used to generate the time-series with voxel-by-voxel B1 + correction for estimating T1/T2/PD maps, while the quantitative MWF map was derived from the reconstructed first time-point ViSTa image I(ViSTa) and the PD map I(PD): MWF = I(ViSTa) I(PD) •S(myelin_water) reconstructed, allowing us to reconstruct the first time-point image (ViSTa signal) and leverage the encoding and SNR-averaging from all other time points.The implementation of the ViSTa-MRF acquisition and joint subspace reconstruction enabled us to directly visualize myelin-water images once the time-series data were reconstructed.It is important to highlight that the myelin-water signal evolution throughout the MRF sequence (as shown in Figure 1(C)) is markedly different from that of WM and GM signals throughout the entire sequence.This unique behavior of the myelin-water signal, along with the subspace reconstruction, effectively utilized the signal and spatial encoding throughout the MRF sequence to differentiate the myelinwater signal from other tissue types and to create a high SNR first ViSTa timepoint data.
(A).To evaluate the fat artifacts, the WE-Rect pulse is compared with the normal non-selective Fermi pulse we used in our previous study.To validate the accuracy of myelin estimation of the proposed ViSTa-MRF method, the proposed method is compared with the standard 2D fully sampled ViSTa sequence with multi-shot spiral readout.The in-plane resolution of the ViSTa is 1mm, slice thickness 5mm.48 spiral interleaves are used to fully sample one slice, results in the total acquisition time of 48× (TI1 560ms+TI2 220ms +TD 380ms)

Figure 3 (
Figure 3(B) shows reconstructed 1mm-iso T2 and MWF maps acquired from a healthy adult using the original FAs and the CRLB-optimized FAs.The red arrows indicate the CRLB-optimized results achieve higher SNR in MWF maps.The zoom-in figures demonstrate that the CRLB-optimized ViSTa images exhibit higher SNR and better visualization of detailed structures in the cerebellum than the ViSTa-MRF images with the original FAs.

Figure 4 (
Figure 4(A) shows a representative time-resolved 1mm-iso MRF-volume after subspace reconstruction using the original fermi-pulse and the WE-Rect pulse.As yellow arrows indicate, the fat artifacts are much mitigated using the WE-Rect pulse.

Figure 4 (
Figure 4(B) shows the comparison between a fully sampled standard 2D-ViSTa sequence (56s/slice) and ViSTa-MRF acquisition (1.3s/slice) with subspace reconstruction, where the results are highly consistent, demonstrating the feasibility in leveraging the joint-spatiotemporal encoding information for highly accelerated ViSTa-

Figure
FigureS1shows a representative slice of T1 and T2 maps estimated from standard MRF and ViSTa-MRF methods.The comparison between the 1mm ViSTa-MRF and the standard MRF sequences demonstrates that the quantitative T1 and T2 maps estimated from ViSTa-MRF are highly consistent with the standard MRF sequence.

Figure 5 (
Figure 5(A) shows the 5-minute whole-brain 1mm-iso T1, T2 and MWF maps in coronal views, where the MWF values for a healthy adult shown in Figure 5(B) from

Figure 7 (
Figure 7(A) shows the estimated 1mm-iso whole-brain T1, T2, and MWF maps of 4months, 12-months babies and a reference 22-year-old adult.As shown in Figure 7(B), a custom-built tight-fitting 32-channel baby coil (62) is used to acquire datasets for improved SNR.The estimated T1 and T2 values of white-matter and gray-matter decrease while the estimated MWF of white-matter increases with brain development, indicating brain dynamic process of myelination, as shown in Figure 7(C).

Figure 9
Figure9shows the 0.50mm-iso ViSTa-MRF results of the post-mortem brain samples.Figure9(A) shows quantitative T1, T2, MWF and PD maps obtained from an ex-vivo 5-month infant brain.The zoom-in figure in Figure9(A) reveals decreased T1, T2, PD, and increased MWF values (indicated by red arrows) in the lines of Baillarger within cortical layers, reflecting the higher myelination level in the cortex.Figure9(B)shows ViSTa-MRF results of the 69-year-old post-mortem brain sample.The decreased T1 and PD and increased MWF values (indicated by black arrows) were detected in the lines of Gennari in V1 region, reflecting the high myelination in Layer IV of the cortex, which are consistent with the high-resolution T2-weighted reference images.As red arrow indicated in Figure9(B), the "dark dots" in MWF and increased T1 and T2 values imply the de-myelination in this region in the aging brain.These findings align with results from other studies(63)(64)(65).
While the standard ViSTa sequence utilizes a single readout to maximize the signal with 90° excitation, the ViSTa-MRF acquisition employs continuous readouts to leverage the myelin-water component and achieve SNR-averaging across all time-points with the subspace reconstruction.To strike a balance between high SNR in the first time-point and distinct signal evaluation of the myelin-water component in the continuous readouts, CRLB optimization was employed for the flip-angle train of ViSTa-MRF.Consequently, our in vivo comparison revealed improved SNR in the ViSTa image when compared to the non-optimized protocol.Furthermore, we also applied the ViSTa-MRF sequence for infant scans to quantitatively investigate infant brain development.Given the rapid changes in relaxation times during the development of infant brains, our future work will involve calculating the CRLB for age-specific T1 and T2 values of myelin-water, white matter, and gray matter.This optimization will enable us to tailor the infant scan protocol to different ages of infants, ensuring accurate and sensitive assessments of brain development.

Figure 1 .Figure 2 .
Figure 1.(A) Sequence diagram of 3D ViSTa-MRF.(B) Extended phase graph (EPG) simulation of the first time-point ViSTa signal.The myelin-water signal with short-T1 is preserved in the ViSTa signal while the white-matter (WM), gray-matter (GM) and CSF are suppressed, which enables direct myelin-water imaging.(C) Simulated signal curves of myelin-water, WM, GM and CSF for the ViSTa-MRF sequence.FA: flip angle

Figure 3 .
Figure 3. (A) Original and CRLB-optimized flip angles (FA) of the ViSTa-MRF protocol.(B) T2 and ViSTa Comparisons between original ViSTa-MRF and CRLBoptimized ViSTa-MRF sequence.The zoom-in figures demonstrate that the CRLBoptimized ViSTa images exhibit higher SNR and better visualization of detailed structures in the cerebellum than the original ViSTa images.

Figure 4 .
Figure 4. (A) Comparison of a representative MRF volume using non-selective fermi pulse and the Water-Excitation Rectangular (WE-Rect) pulse.As yellow arrows indicate, the fat artifacts are mitigated using the WE-Rect pulse.(B) The comparison between a fully sampled standard 2D ViSTa sequence and ViSTa-MRF with subspace reconstruction.(C) Pre-scanned and spatial-smoothed B1 + map and (D) reconstructed T1, T2, and MWF without (first row) and with (second row) B1 + correction.With B1 + correction, the estimated T2 and MWF maps in regions indicated by the red arrows are more uniform compared to the results without B1 + correction.

Figure 5 .
Figure 5. (A) Whole-brain 1-mm iso T1, T2 and MWF maps in coronal views.(B) Two representative slices of MWF maps in axial views.

Figure 7 .
Figure 7. (A) Whole-brain 1.0 mm isotropic T1, T2 and MWF maps of a 4-month infant, a 12-month infant and an adult as a reference.(B) The baby data were acquired with a custom 32-channel tight-fitting baby coil.(C) Both T1 and T2 values decrease while the MWF increases with brain development, indicating the brain dynamic process of myelination.

Figure 9 .
Figure 9. 0.50-mm iso T1/T2/PD and MWF maps of (A) a coronal slab obtained from a 5-month-old post-mortem brain and (B) a left occipital lobe obtained from a 69-yearold post-mortem brain.The total acquisition time is 57 minutes.T1/T2/MWF/PD maps shows (A) the myelinated lines in cortical layers and (B) lines of Gennari in V1 region with decreased T1 & PD and increased MWF values (indicated by black arrows) and the "dark dots" in MWF and increased T1 and T2 values (indicated by red arrows).

Figure S2 .
Figure S2.T1 comparison between 1mm and 0.66-mm data.The higher resolution in the 0.66-mm dataset can aid in better visualization of subtle brain structures such as small sulci and the periventricular space as indicated by the red arrows.
66 mm isotropic whole-brain ViSTa-MRF sequences on one 3T GE Premier scanner and one ultra-high-performance (UHP) scanner (GE from each participant's parents.Scans were scheduled approximately 1 hour after the infant's bedtime, for a 2-hour window to allow sufficient time for the infant to fall asleep and/or restart scans if the infant awakens.MR- 3, total acquisition time: 6 minutes 20 seconds.The experiments were performed on a 3T GE UHP scanner with the approval of the institutional review board.Written informed consent was obtained